The goal of this R21 Exploratory proposal is to determine how multicellular organs and organisms survive DNA damage by ionizing radiation, using Drosophila melanogaster as a model. Cell cycle checkpoints and DNA repair appear essential for single cells to survive DNA damage. Our work in Drosophila suggests an additional requirement in the multi-cellular context, that of growth (increase mass). We hypothesize that survival accompanies the removal of damaged cells via apoptosis, increased growth, and compensatory proliferation to replace cells lost to death. The mechanisms that contribute to radiation survival in a multicellular context will be dissected in 3 Aims. Aim 1 will take advantage of our finding that growth inhibition kills checkpoint mutants preferentially over wild type following irradiation. Thus, a screen to identify chemicals that selectively kill irradiated checkpoint mutants but spare irradiated wild type larvae will be performed in order to identify new tools for studying radiation survival in a multi-cellular context. Aim 2 will determine the mechanism of action of chemicals identified in Aim 1. Specifically, effects on cell proliferation, cell death, DNA repair and cellular growth will be assayed. Aim 3 will compare the effect of a subset of chemicals from Aim 1 on radiation sensitivity of Drosophila larvae that are mutant for another checkpoint gene. This Aim tests the hypothesis that tissues lacking different checkpoint functions rely on different cellular mechanisms to survive radiation. If so, we expect to find that radiation sensitizers for one mutant will be ineffective against another mutant. Understanding radiation survival in a multicellular context could help identify potential therapies for when we do not want cells to survive irradiation, such as in the treatment of cancer.